PROJECT SUMMARY Elderly pneumonia survivors are at increased risk of developing skeletal muscle atrophy that impairs mobility, dementia, and cognitive dysfunction, which are perhaps the most debilitating limitations to health-span in the elderly. We found critical features of this multiple organ dysfunction after pneumonia are recapitulated in mice, allowing us to use mouse models to elucidate mechanisms that can be targeted for therapy. In the first cycle of this award, we found that a systemic increase in IL-6 during influenza A-induced pneumonia was necessary for upregulation of the E3-ubiquitin ligase atrogin-1 and muscle wasting in both young and aged animals. While muscle function was rapidly restored in young animals, we never observed it to recover in older animals even months after pneumonia. We observed that muscle satellite cells necessary for muscle repair failed to proliferate after pneumonia in aged, but not in young animals, which was associated with decreased expression of the scavenger receptor Mertk. Genetic disruption of genes required for phagocytosis (Mertk, C3, Cx3cr1) in young animals phenocopied the impaired satellite cell proliferation after influenza A pneumonia in aged animals. In parallel studies in the brain, we found that while young mice recover cognitive function after influenza A infection, older animals develop persistent neurocognitive impairment. Highly sensitive transcriptomic profiling of flow sorted microglia showed aged microglia exhibited decreased expression of scavenger receptors, including Mertk. This was associated with reduced expression of genes related to axonogenesis, learning and memory in whole brain transcriptomes from aged compared with young animals after influenza A-induced pneumonia. Tissue resident muscle macrophages and microglia from young mice robustly activated the integrated stress response (ISR) after influenza A infection as evidenced by increased expression of Activating Transcription Factor-4 (Atf4) and molecular chaperones, but aged mice lacked this response. These preliminary data support our hypothesis that age-related loss of scavenger receptor function impairs phagocytosis in tissue resident macrophages necessary for the molecular and physiologic recovery of skeletal muscle and cognitive function after pneumonia. We will determine whether these age-related changes can be reversed by inhibition of mitochondrial complex I via the ISR and/or ATF4 in two interrelated specific aims: Aim1. To determine whether scavenger receptor activity in resident skeletal muscle macrophages and microglia and is necessary for the recovery of cognitive and skeletal muscle function after influenza A- induced pneumonia. Aim 2. To determine whether modulation of mitochondrial metabolism, the integrated stress response and/or ATF4 can restore scavenger function of the microglia and skeletal muscle macrophages to improve cognitive and motor function in aged mice after pneumonia.